Continuous flow synthesis method for the manufacture of isoniazid

Abstract

A multistep continuous flow synthesis method for the manufacture of isonicotinyl-hydrazide (Isoniazid) comprising reacting 4-cyano pyridine with NaOH at a specified molar ratio and temperature range to produce the intermediate isonicotinamide, which intermediate is reacted with hydrazine hydrate, without isolation thereof, at a specified molar ratio and temperature range to produce isonicotinyl-hydrazide (Isoniazid) in a yield greater than about 90%.

The invention claimed is: 
     
         1 . A multistep continuous microreactor flow synthesis method for the manufacture of isonicotinyl-hydrazide of Formula 1 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         a) in a first microreactor, or a first part of a suitable microreactor setup, reacting 4-cyano pyridine of Formula 12 
       
       
         
           
           
               
               
           
         
         in a mixture of water and alcohol, with NaOH in a molar ratio of 4-cyano pyridine:NaOH of about 1:0.2 to about 1:0.4 at a temperature of about 95° C. to about 105° C. to produce the intermediate isonicotinamide of Formula 13 
       
       
         
           
           
               
               
           
         
         b) in a second microreactor, or a second part a suitable microreactor setup, which is in fluid communication with the first microreactor, or the first part of the microreactor, reacting the intermediate isonicotinamide of Formula 13 with hydrazine hydrate in a molar ratio of 4-cyano pyridine:hydrazine hydrate of about 1:1.75 to about 1:2.50 at a temperature of about 100° C. to about 120° C., 
         wherein the reaction in step a) has a residence time of about 10 to about 32 minutes, the reaction in step b) has a residence time of about 10 to about 25 minutes, and the method produces the isonicotinyl-hydrazide of Formula 1 in yields greater than about 90%. 
       
     
     
         2 . The method according to  claim 1 , wherein in step a) the 4-cyano pyridine is dissolved in a mixture of water and methanol. 
     
     
         3 . The method according to  claim 1 , wherein the water and alcohol mixture has a ratio of alcohol:water of about 7:3. 
     
     
         4 . The method according to  claim 1 , wherein in step a) the molar ratio of 4-cyano pyridine to NaOH is about 1:0.2. 
     
     
         5 . The method according to  claim 1 , wherein in step a) the temperature is about 95° C. to about 100° C. 
     
     
         6 . The method according to  claim 5 , wherein in step a) the temperature is about 95° C. 
     
     
         7 . The method according to  claim 1 , wherein in step a) the residence time is about 10 to about 15 minutes. 
     
     
         8 . The method according to  claim 7 , wherein in step a) the residence time is about 10 minutes. 
     
     
         9 . The method according to  claim 1 , wherein in step b) the molar ratio of 4-cyano pyridine:hydrazine hydrate is about 1:1.75 to about 1:2.25. 
     
     
         10 . The method according to  claim 9 , wherein in step b) the molar ratio of 4-cyano pyridine:hydrazine hydrate is about 1:2.0. 
     
     
         11 . The method according to  claim 1 , wherein in step b) the temperature is about 100° C. to about 115° C., or about 105° C. to about 115° C. 
     
     
         12 . The method according to  claim 11 , wherein in step b) the temperature is about 105° C. 
     
     
         13 . The method according to  claim 12 , wherein in step b) the residence time is about 10 to about 20 minutes. 
     
     
         14 . The method according to  claim 13 , wherein in step b) the residence time is about 10 minutes. 
     
     
         15 . The method according to  claim 1 , wherein the total multistep continuous flow synthesis method yield for isonicotinyl-hydrazide from 4-cyano pyridine is greater than about 92%, greater than about 94%, or greater than about 95%. 
     
     
         16 . The method according to  claim 15 , wherein the total multistep continuous flow synthesis method yield for isonicotinyl-hydrazide from 4-cyano pyridine is about 96%.